While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and deaths are on the rise, with the five year survival rate worse today than three decades ago. Inadequate sensitivity to chemotherapy is a primary cause of therapeutic failure. To improve patient outcomes, we must identify the appropriate molecularly targeted agents to combine with chemotherapy, a concept we term molecularly enhanced chemotherapy. Such combinations must be based upon a mechanistic understanding of tumor cell vulnerabilities which can be exploited to create synergism and synthetic lethality. Our objective in this renewal application is to capitalize on the most common mutation in high-risk endometrial cancers, p53, to design new and more active combinatorial regimens that can improve response in the upfront setting. p53 mutations alter the master regulators of cell cycle checkpoints in predictable yet distinct ways which can be capitalized upon to overcome resistance to chemotherapy using targeted agents that block compensatory survival pathways. Therefore, our central hypothesis is that molecular inhibitors of key master regulators, chosen based upon the knowledge of the p53 mutational status, synergize with chemotherapy and promote catastrophic tumor cell death. We term this concept molecularly enhanced chemotherapy. In Specific Aim #1, we will determine the role of p53, other cell cycle checkpoint controllers and angiogenic markers as predictors of sensitivity when anti-angiogenic molecular inhibitors are combined with chemotherapy. This aim incorporates clinical specimens from a completed trial, GOG/NRG 86P, the first national study to combine molecular inhibitors with chemotherapy for advanced/recurrent endometrial cancer. In Specific Aim #2, we will assess the mechanisms of resistance to therapy as defined by outcomes from NRG/GOG 86P and identify alternative molecularly enhanced combinations. In Specific Aim #3, we will interrogate the function of p53 mutations that are variants of unknown significance (VUS) to define the best therapy for these tumors. The major goal of this aim is to bin VUS from NRG/GOG 86P into functional categories and understand the impact of recurrent VUS on cell transcription and cell cycle regulation. At the completion of these studies, it is our expectation that we will have designed and tested synergistic drug combinations tailored for specific endometrial cancer subtypes. These studies will make a significant positive impact on the field by enhancing the design and choice of therapy for future endometrial cancer clinical trials.